The BIT1 cell death pathway as a novel regulator of egfr-TKI-induced apoptosis and resistance - principal investigator/program director (last, first, middle): biliran JR., hector the BIT1 cell death…

The National Cancer Institute, part of the Department of Health and Human Services National Institutes of Health, awarded $150,000 to Xavier University of Louisiana on August 20, 2026, under the Cancer Biology Research program (CFDA 93.396) to investigate the BIT1 cell death pathway as a regulator of EGFR-TKI-induced apoptosis and resistance in non-small-cell lung cancer.

The research, led by Principal Investigator Hector Biliran Jr., examines how the mitochondrial BCL2 transcription inhibitor 1 (BIT1) protein governs caspase-independent apoptosis triggered by epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Prior work at Xavier has demonstrated that BIT1 exerts cell death function in NSCLC through inhibition of the anti-apoptotic TLE1 nuclear function. The project investigates BIT1 activation in TKI-resistant NSCLC and its suppression of TLE1-mediated pro-survival programs in drug-tolerant persister cells, which are precursors to drug-resistant cells. The central hypothesis is that enhancing BIT1 cell death pathway function will improve EGFR-TKI sensitivity by disrupting TLE1-mediated survival signals.

Performance occurs in New Orleans, Louisiana, with a period of performance from August 20, 2026, through July 31, 2030. The Cancer Biology Research program funds fundamental research on cancer cause and nature to advance prevention, detection, diagnosis, and treatment methods, including cancer cell biology, immunology, hematology, DNA and chromosomal aberrations, tumor biology and metastasis, and structural biology and molecular applications.

The BIT1 cell death pathway as a novel regulator of egfr-TKI-induced apoptosis and resistance - principal investigator/program director (last, first, middle): biliran JR., hector the BIT1 cell death pathway as a novel regulator of egfr-TKI-induced apoptosis and resistance in nsclc epidermal growth factor receptor tyrosine kinase inhibitors (egfr-tkis) are the gold standard for treating egfr mutant in non-small-cell lung cancer (nsclc) tumors. While these drugs offer significantly improved outcomes compared to traditional chemotherapy, egfr-TKI therapy including the latest third-generation agents invariably leads to the emergence of acquired resistance due to tumor evasion of egfr-TKI-induced apoptosis. A comprehensive understanding of the cell death mechanisms governed or influenced by egfr-tkis is currently lacking. The mitochondrial BCL2 transcription of inhibitor 1 (BIT1) protein is part of an integrin regulated cell death pathway that upon its release to the cytosol triggers caspase-independent apoptosis. This lab's prior r-15 and R16 work has provided evidence that BIT1 exerts cell death function in nsclc via caspase-independent inhibition of the anti-apoptotic TLE1 nuclear function. Our preliminary data indicates that egfr-TKI triggers BIT1 cytosolic release independent from mitochondrial outer membrane permeabilization (momp), and BIT1 ablation attenuates egfr-TKI-induced apoptosis. BIT1 activation in TKI-resistant nsclc triggers apoptosis primarily through caspase-independent TLE1 suppression, with new evidence indicating secondary mitochondrial engagement. In egfr-TKI-induced drug tolerant persister cells (dtps) which give rise to drug-resistant cells, the TLE1 transcriptional program is activated to promote survival and block BIT1 apoptosis. Based on these compelling findings, our central hypothesis is that the BIT1 cell death pathway enhances egfr-TKI sensitivity by disrupting the TLE1-mediated pro-survival program in the nucleus and secondarily engaging mitochondrial apoptotic factors, and BIT1 activation can enhance therapeutic efficacy and overcome resistance to egfr-tkis. To test this hypothesis, we will address the following specific aims: 1) elucidate the mechanisms by which the momp- independent BIT1 cell death pathway enhances egfr-TKI sensitivity by disrupting the TLE1 survival transcriptional program; 2) define the mechanisms by which the BIT1 pathway overcomes egfr-TKI tolerance and resistance, and identify novel therapeutic targets; and 3) determine the in vivo efficacy of BIT1 pathway activation in overcoming egfr-TKI resistance and minimal residual disease (MRD) in egfr-mutant nsclc. These proposed studies, while serving as a platform to engage undergraduate students in innovative research, will offer new therapeutic opportunities to enhance egfr-TKI efficacy and block the emergence of egfr-TKI resistance in egfr mutant nsclc.